Are You Confident of the Diagnosis?
Lipoid proteinosis (LP) is an autosomal recessive hereditary disease that equally affects males and females.
LP is characterized by the deposition of hyaline material in the skin, mucosa, and viscera. Laryngeal infiltration may result in a hoarse cry. Skin and mucous membrane changes become apparent clinically, and the disease typically follows a slowly progressive, often benign course, yet it may involve virtually any organ. From a clinical perspective, the features may be protean. Two main groups of clinical manifestations are described: dermatologic and neurologic.
Symptoms vary greatly between affected individuals, even those within the same family. Usually the disease starts in early infancy with a hoarse voice due to thickening of the vocal cords. Lesions and scars also appear on the skin, usually the face and the distal parts of the limbs. Skin may be easily damaged as a result of only a minor trauma or injury, leaving many blisters and additional scars. Poor wound healing and the scarring continue to increase as the patient ages, leaving the skin with a waxy appearance. The skin is also usually very dry and wrinkly. White or yellow infiltrates form on the lips, buccal mucosa, tonsils, uvula, epiglottis, and the frenulum of the tongue (Figure 1).
Frequently upper respiratory tract infections occur, sometimes requiring tracheostomy to relieve the symptoms. Abundant frenulum thickening can restrict tongue movement and result in speech impediments. Other mucocutaneous changes may include warty skin papules, hair loss to alopecia, parotitis, corneal ulceration, focal degeneration of the macula, nail dystrophy and dental anomalies. Some inter- and intrafamilial variability in skin phenotype was seen, but a hoarse voice was a universal finding.
About 50% to 75% of the diagnosed cases of Urbach-Wiethe disease also show bilateral symmetrical calcifications on the medial temporal lobes, often affecting amygdala, periamygdaloid gyri, and hippocampi. Brain damage develops over time and is associated with the development of mental retardation and epileptic seizures. Damage to the amygdala, a part of the brain that regulates emotions and perceptions, leads to difficulties in discriminating facial expressions and in making realistic judgments about the trustworthiness of other people. Some patients also exhibit neuropsychiatric abnormalities, eg, autism, schizophrenia, mood, anxiety, and psychotic disorders.
Characteristic findings on physical examination
Typically diagnosed by its clinical dermatologic manifestations, particularly the beaded papules on the eyelids (Table I).
|Beaded eyelid papules|
|Skin hyperkeratosis on the palms|
|Warty papules on hands and limbs|
|Acne-like pitted scars of the face|
|Waxy nodules and scarring on the elbows|
|Thickening of vocal cords|
|Hardening of brain tissue in the medial temporal lobes|
Expected results of diagnostic studies
Skin biopsy usually is subdivided for light microscopy, immunohistochemistry, and immunofluorescence microscopy and transmission electron microscopy.
– basket-woven hyperkeratosis
– prominent periodic acid-Schiff’s (PAS) reagent staining (glycoprotein) at the dermal epidermal junction and around dermal blood vessels
– an anti-type IV collagen antibody or anti-type VII collagen antibody labeling shows bright, thick bands of staining at the dermal–epidermal junction and around blood vessels, consistent with basement membrane thickening at these sites
– dermal blood vessels surrounded by multilaminated concentric rings of basement membrane (concentric reduplication of basement membrane)
– abnormal vacuoles in skin fibroblasts
The genome-wide linkage analysis shows:
– Direct sequencing of exon 7 of ECM1 in an affected South African patient reveals a C T transition at nucleotide 826 that converts a glutamine residue (CAG) to a stop codon (TAG); the mutation is designated Q276X.
– Verification of the mutation Q276X by restriction endonuclease digestion with BfaI (New England BioLabs, Hitchen,UK). Wild-type PCR product (–/–) spanning exon 7 and flanking introns (548 bp) is digested into products of 451 and 97 bp, consistent with a solitary cut site for BfaI. In patients homozygous for the mutation Q276X (+/+), the PCR product is digested into fragments of 332, 119 and 97 bp in size, as the mutation introduces a new recognition site for this enzyme. In individuals heterozygous for 276X (+/–), four digested fragments (451, 332, 119 and 97 bp) are present.
– Six different mutations are identified in the ECM1 gene in patients with LP. All patients are homozygous for a single mutation. Four mutations are located within the differentially spliced exon 7 (Q276X, Q346X, W359X and 1019delA). The other mutations comprise a frameshift mutation in exon 6 (501insC) and a 1163 bp deletion starting 34 bp into intron 8 and encompassing all of exon 9, intron 9, exon 10 (including the termination codon) and part of the 3′-UTR.
The main differential diagnoses of LP includes the following:
– erythropoietic protoporphyria — a history of photosensitivity at an early age with the subsequent development of thickened skin and scars in exposed sites;
– lichen amyloidosis — pruritic lesions, usually on the shins, and demonstrates amyloid on histology;
– scleromyxedema — usually distributed on the extremities and face, a histology demonstrating mucin, and an associated paraproteinemia;
– xanthomas — may be associated with hyperlipidemia.
Who is at Risk for Developing this Disease?
Lipoid proteinosis (LP) is a hereditary disease that equally affects males and females. Nearly a quarter of all reported cases have been in the Afrikaner population of South Africa, but the disease is increasingly being reported from other parts of the world including India and the Northern Cape province of South Africa, including Namaqualand, where it occurs predominantly in a population of mixed Khoisan and European origin in which a founder effect has long been suspected.
Family history — Autosomal recessive disease
What is the Cause of the Disease?
It is now proven that lipoid proteinosis is an autosomal recessive condition. Individuals can be carriers of the disease and show no symptoms. The disease is caused by loss-of-function mutations to chromosome 1 at 1q21, the extracellular matrix protein 1 (ECM1) gene. The dermatologic symptoms are caused by a buildup of a hyaline material in the dermis and the thickening of the basement membranes in the skin.
LP is mapped to 1q21q, which identifies the ECM1 gene as the mutated gene in the disorder. Human ECM1 encodes a glycoprotein of unknown function. It has been thought to have a role as a negative regulator of endochondral bone formation, inhibiting alkaline phosphatase activity and mineralization. In addition, it has been implicated in aspects of keratinocyte differentiation, tumor biology and angiogenesis, selectively stimulating endothelial cell proliferation and promoting blood vessel formation.
ECM1 is expressed as alternatively spliced transcripts 1.8 kb ECM1a and 1.4kb ECM1b. ECM1a is predominantly present in the placenta and heart (but also in the liver, small intestine, lung, ovary, prostate, testis, skeletal muscle, pancreas, kidney and skin) and ECM1b is found in skin and tonsils. The ECM1 gene is located close, but centromeric, to the epidermal differentiation complex on 1q21 and an association between keratinocyte differentiation and expression of the ECM1b transcript was demonstrated.
The longer isoform, ECM1a, is of more fundamental biological importance. The lack of ECM1a leads to defective protein binding. ECM1 has a pattern of cysteine repeats similar to the ligand binding loops present in serum albumins and, therefore, if ECM1 normally binds type IV collagen, the lack of this potentially regulatory or stabilizing protein–protein interaction in LP could then result in increased type IV collagen expression and the typical histopathologic changes. Failure to bind other non-collagenous proteins also accounts for the hyaline material deposition in skin and other tissues.
The accent is nowadays given to the ECM1 function, particularly the ECM1a isoform. The loss of ECM1 expression could explain the protean clinical manifestations in the disorder. Meanwhile, it correlates with other inherited disorders such as infantile systemic hyalinosis (which may have clinical overlap with LP), which may also be introduced into the spectrum of ECM1 pathology. Delineation of ECM1 as the LP gene may provide new insight into the pathogenesis of some acquired or autoimmune disorders such as lichen sclerosus, systemic sclerosis or graft-versus-host-disease that may be associated with hyperkeratosis of the epidermis and hyaline changes in the dermis.
The ultrastructural changes affecting basement membrane material seen around blood vessels in LP are reminiscent of those occurring in diabetes mellitus, systemic sclerosis and porphyria. These observations also indicate a role for ECM1 in other aspects of angiopathy or angiogenesis. It plays an important role in skin adhesion, epidermal differentiation, wound healing and scarring and defines it as an important secreted protein with diverse biological functions.
Systemic Implications and Complications
Restrictive respiratory failure
To date, there is no cure for Urbach-Wiethe disease. Multidisciplinary management is required for all patients.
Symptomatic treatment to relieve the symptoms of skin and mucosal thickening. Laser microlaryngoscopy, dissection and excision of deposits may be used to preserve and improve the voice and obviate the need for tracheotomy in most cases.
Alleviation of skin manifestations can be achieved through pathogenetic therapy.
Oral dimethyl sulfoxide (DMSO)
Anecdotal cases were treated with long-term oral DMSO (60mg/kg/d). At the end of an average treatment time of 3 years, most of the patients showed no imrovement and DMSO had to be withdrawn. One patient is reported to show progression of the disease with worsening hoarseness and onset of dyspnea, requiring surgical removal of vocal cord infiltrates.
Long-term therapy with 1mg/kg/d with beneficial effect on voice hoarseness and skin lesions
In addition to its immunosuppressive and anti-inflammatory effects, penicillamine also impairs fibroblast proliferation and inhibits the formation of the cross-links in collagen and elastin fibers. One case of lipoid proteinosis was treated with 600mg/day of D-penicillamine for 2 years. The patient had improved clinically and histopathologically by the end of this treatment, thus proving D-penicillamine as a promising agent, even in low doses, for the treatment of the disease.
Acitretin therapy (0.5 to 1mg/kg/d) may show some regression and softening of skin lesions. However, no histopathologic change in PAS-positive deposition could be detected. Probably, acitretin may be helpful for patients, especially those who complain about hyperkeratosis.
Surgical procedures for the vocal cords and beaded papules: Dermabrasion, carbon dioxide laser surgery
Neurologic symptoms: All conventional anticonvulsants can be used.
Obstructive respiratory failure: Tracheostomy
Optimal Therapeutic Approach for this Disease
Possible future molecular therapy
No laboratory findings are consistently abnormal. The erythrocyte sedimentation rate might be elevated as a result of increased prodiction of alpha- and beta-globulins.
It is suggested that raised serum alkaline phosphatase could be the result of increased lipo-glycoprotein synthesis and that one long-term consequence of this is endocranial calcification. It is also hypothesized that in a family in which lipoid proteinosis occurs in one member, raised serum alkaline phosphatase may perhaps be taken as an indication of latent lipoid proteinosis in an otherwise clinically normal member.
Porphyria should be excluded by appropriate blood and urine analysis.
The ECM1 gene can be detected by polymerase chain amplification and direct nucleotide sequencing. A prospective diagnostic test is the immunolabeling of affected tissue with polyclonal antibodies against the ECM1 protein.
Direct laryngoscopy and videolaryngoscopical examination
Thickened epiglottis and false cords, swollen arytenoids and aryepiglottic folds are usually visualized. The vocal folds are mobile and minimally hyperemic and edematous. Yellowish, mildly ulcerated lesions surrounded with hyperemic mucosa in soft palates can be seen.
Acoustic parameters such as jitter, shimmer and noise/harmonics ratio are ususally higher than normal. Noise components suppress harmonics seen in spectrogram. First and second formants cannot be discerned. Third and fourth formants cannot be observed. With evaluation of patient’s voice by GRBAS scale: G, 3; R, 2; B, 1; A, 0; S, 3. The analysis proves the hoarseness and roughness of the voice.
Pathognomonic finding of the brain is bilateral, intracranial, bean-shaped calcifications within the hippocampal region of the temporal lobes.
– LP has a stable or slowly progressive course.
– Children may have behavioral or learning difficulties, along with seizures.
– Obstruction in the throat may require a tracheostomy.
– Mortality rates in infants and adults are slightly increased because of problems with throat obstructions and upper respiratory tract infections.
– Usually the disease is not life threatening and patients do not show a decreased life span.
Unusual Clinical Scenarios to Consider in Patient Management
The discovery of the mutations of the ECM1 gene has opened the possibility of gene therapy or a recombinant ECM1 protein treatment, but neither of these options is currently available.
What is the Evidence?
Urbach, E, Wiethe, C. “Lipoidosis cutis et mucosae”. Virchows Arch Pathol Anat. vol. 273. 1929. pp. 285-319. (The original description of the disease.)
Stine, O, Smith, K. “The estimation of selection coefficients in Afrikaaners: Huntington disease, porphyria variegata, and lipoid proteinosis”. Am J Hum Genet. vol. 46. 1990. pp. 452-8. (Genetic analysis of individuals to look at the incidence of rare disorders including lipoid proteinosis.)
Findlay, G, Scott, FP, Cripps, DJ. “Porphyria and lipid proteinosis”. Br J Dermatol. vol. 78. 1966. pp. 69-80. (Discussion on lipoid proteinosis and the characteristics that are similiar and unique to porphyria.)
Olsen, DR, Chu, ML, Uitto, J. “Expression of basement membrane zone genes coding for type IV procollagen and laminin by human skin fibroblasts in vitro: elevated a 1 (IV) collagen mRNA levels in lipoid proteinosis”. J Invest Dermatol. vol. 90. 1988. pp. 734-8. (Genetic analysis of patients with lipoid proteinosis, specifically looking at the expression of type IV collagen.)
Hamada, T, Irwin, M, cLean, WH, Ramsay, M, Ashton, G, Nanda, A, Jenkins, T. “Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1)”. Hum MolGenet. vol. 11. 2002. pp. 833-40. (Discovery of the genetic mutation in lipoid proteinosis.)
Smits, P, Poumay, Y, Karperien, M, Tylzanowski, P, Wauters, J, Huylebroeck, D. “Differentiation-dependent alternative splicing and expression of the extracellular matrix protein 1 gene in human keratinocytes”. J Invest Dermatol. vol. 114. 2000. pp. 718-24. (Discusses the role of the defective gene in the pathogenesis.)
Han, Z, Ni, J, Smits, P, Underhill, CB, Xie, B, Chen, Y. “Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells”. FASEB J. vol. 15. 2000. pp. 988-94. (Discussion on the function of the ECM1 protein.)
Dinakaran, S, Desai, SP, Palmer, IR, Parsons, MA. “Lipoid proteinosis: clinical features and electron microscopic study”. Eye. vol. 15. 2001. pp. 666-8. (Excellent review and analysis of lipoid proteinosis and the findings under electron microscopy.)
Kleinert, R, Cervos-Navarro, J, Kleinert, G, Walter, GF, Steiner, H. “Predominantly cerebral manifestation in Urbach–Wiethe’s syndrome (lipoid proteinosis cutis et mucosae): a clinical and pathomorphological study”. Clin Neuropathol. vol. 6. 1987. pp. 43-5. (A look at lipoid proteinosis from the neurologic perspective. Discusses the clincal neurologic findings seen in the disease.)
Kaya, TI, Kokturk, A, Tursen, U, Ikizoglu, G, Polat, A. “D-penicillamine treatment for lipoid proteinosis”. Pediatr Dermatol. vol. 19. 2002. pp. 359-62. (Report on treating lipoid proteinosis with D-penicillamine.)
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